JPH07188024A - Cerebral circulatory disorder therapeutic agent - Google Patents

Abstract

PURPOSE:To obtain a therapeutic agent for cerebral circulation disorders comprising 5,6,7,8-tetrahydroneopterine as an effective component, being fast acting and having an inhibiting activity against tissue injuries caused by cerebral circulation disorders. CONSTITUTION:This therapeutic agent for cerebral circulation disorders comprises 5,6,7,8-tetrahydroneopterine expressed by the formula as an effective component. The compound of the formula inhibits excessive oxygen supply to tissues and excessive delivery of excitatory nervous transfer material caused by the disorders of cerebral ischemic recirculation and death of nervous cells caused by cerebral ischemic disorders. For example, it is effective as a therapeutic agent for cerebrovascular disorders such as cerebral infarction, cerebral hemorrhage, etc., consciousness disorders caused by the same and dementia. As for formulations, it is used in the forms of liquid or that filled in liposome and capsules in the case of injections. When it is orally used, it is used as tablets, capsules, solutions, powders, fine granules, granules, pills and suspensions.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a preparation containing 5,6,7,8-tetrahydroneopterin (hereinafter abbreviated as NPH4) as an active ingredient and effective for treating cerebral circulation disorders.

[0002]

2. Description of the Related Art NPH4 has been found to have an excellent effect on the treatment of diabetes (type I), ischemia-reperfusion injury, liver injury, etc. (Japanese Patent Application No. 04-175917). Also, N
It has been confirmed that PH4 is also effective in suppressing cancer metastasis and treating side effects of anticancer agents (Japanese Patent Application No. 04-304525).

However, it is not found in academic journals or patent publications that NPH4 is effective for cerebral circulation disorders.

[0004]

Stroke is currently the leading cause of death, and a therapeutic agent therefor is widely sought.
It is said that impaired blood circulation in the brain is involved in the etiology of these diseases. Cerebral ischemic injury is caused by hypotension caused by ischemia, decreased energy metabolism due to hypoxia, and further progressed by reperfusion, resulting in memory, learning,
When the emotion and spontaneity are lowered and, in severe cases, dementia and brain death are caused. The progression of such a disease is delayed due to depletion of energy, particularly ATP, disruption of calcium and osmotic homeostasis, generation of free radicals, and excessive release of excitatory neurotransmitters in nerve cells after ischemia. It is derived from the occurrence of neuronal cell death and decreased cell function of.

It is also known that, in addition to stroke, traumatic brain damage due to a traffic accident, myocardial infarction, and cardiac arrest due to angina cause dementia and brain death. In the current emergency medical care, an oxygen mask and a cardiotonic agent are often used together in such cases. However, in this case, high oxygen blood is forcibly transported to the affected area with low blood pressure, low oxygen and low energy, which may rather promote tissue damage in the affected area, which is a problem.

[0006] Furthermore, in the case of cerebral circulatory disorder, simultaneous administration of SOD and catalase has been attempted, but there is a problem in stability, and in the case of long-term administration, anaphylaxis may occur due to the protein. Yes, there is a problem with stability. Then, the subject of this invention is aiming at formulation of the substance which has immediate effect and has the tissue damage suppression activity resulting from the cerebral circulation disorder.

[0007]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventor has found that NPH4 has a tissue damage inhibitory activity due to cerebral circulation disorder, and further has NPH.
Since 4 and its salt have high water solubility, it was clarified that they can be formulated as an injection and completed the present invention.

That is, the present invention has the general formula:

[0009]

[Chemical 2]

A therapeutic agent for cerebral circulation disorders containing NPH4 as an active ingredient. Hereinafter, the present invention will be described in detail. NPH4 has a tissue damage inhibitory activity caused by cerebral circulation disorder, and particularly suppresses excessive tissue oxygen supply and excessive release of excitatory neurotransmitters caused by cerebral ischemia-reperfusion injury, and nerves caused by cerebral ischemia injury. It was found to suppress cell death. As a result, NPH4 is effective as a therapeutic agent for ischemic cerebral tissue disorders, for example, cerebrovascular disorders such as cerebral infarction and stroke, and consciousness disorder and dementia caused by these disorders.

Although NPH4 can be used as it is, it is produced as an inorganic acid salt such as hydrochloride or sulfate, or as an organic acid salt such as camphorsulfonic acid, tartaric acid, malic acid, oxalic acid, and used for injection or oral preparation. Can be the main drug of.
NPH4 is a known method (for example, M. Viscontin
i, R. Provenzale, S. Ohlgart und J. Mallevialle, He
lvetica Chimica Acta -Vol. 53, Fasc. 5 (1970)-Nr.
139, Bernhard Schiriks, Jost H. Bieri und Max Vis
contini, Helvetica Chimica Acta -Vol. 59, Fasc. 1
(1976)-Nr. 27, Rembold, Buschman, (1963), Ber., 9
It can be obtained by the manufacturing method introduced in 6, 1406).

The pharmaceutical dosage form is manufactured by encapsulating in a water solution or liposomes or microcapsules as an injection, and orally, tablets, capsules, liquids, powders, fine granules, granules and pills. , Can be used as a suspension agent. Sterile compositions for injections are prepared by dissolving NPH4 or its salt compound in water for injection as it is, and if necessary, buffering agents such as phosphates, acetates and borates, isotonic agents such as salt and glucose. Agents, benzyl alcohol, soothing agents such as procaine hydrochloride, preservatives, antioxidants such as ascorbic acid, pigments and the like can be added. Natural lecithin,
The drug can be encapsulated in a synthetic lecithin such as dipalmitoyl or distearoylresin, and the liposome can be made into an injection. It can also be used as an oral or injectable preparation by forming a microcapsule coated with ethyl cellulose, polyisobutylene, or the like.

The adjuvants to be mixed with tablets, fine granules, capsules and the like are as follows. Gum arabic, tragacanth, gelatin, sucrose, methyl cellulose, binders such as polyvinylpyrrolidone, lactose, starch, dextrin, microcrystalline cellulose, talc, titanium oxide, excipients such as inorganic salts, carboxymethyl cellulose, sodium alginate , Gelatinized starch, disintegrants such as corn starch, talc, magnesium stearate,
Lubricants such as wax, sugars, sweeteners such as saccharin, citric acid, glutamic acid, peppermint, red oil, flavors such as cherry, in the case of capsules, in addition to the above materials, liquids such as vegetable oils and fats A carrier can be included. If necessary, dyes that are permitted for medicinal purposes are used.

In order to change the physical form of the preparation, known celluloses such as cellulose acetate phthalate and acrylic acid-based materials such as ethyl methacrylic acid acrylate copolymer are used as enteric coating agents. used. The tablets can be coated with shellac and sugar. Liquid preparations such as syrups and elixirs may contain, in addition to the base drug, sucrose or the like as a sweetening agent, methyl or propylparaben as a preservative, a dye and cherry, or a flavoring agent such as orange flavor. Further, if necessary, a surfactant, an emulsifying or suspending agent such as methylcelluloses, gum arabic and tragacanth can be used.

[0015]

EXAMPLES The present invention will be specifically described below with reference to examples. Example 1 Method for producing injection of NPH4 main component preparation Injection (1) 5,6,7,8-tetrahydroneopterin dihydrochloride 12 g (2) Sodium chloride 9 g Components (1) and (2) are distilled water It was dissolved in 1000 ml, dispensed in 1 ml portions into 1000 brown ampoules, replaced with nitrogen gas, and sealed. All steps were performed under sterile conditions.

Example 2 Method for manufacturing tablets of NPH4 main component preparation (1) 5,6,7,8-tetrahydroneopterin 10 g (2) Lactose 90 g (3) Corn starch 29 g (4) Magnesium stearate 1 g 1000 tablets 130 g Ingredients (1), (2) and 17 g of (3) are mixed to give 7 g of ingredients
Granulate with the paste made from (3), add 5 g of ingredient (3) and ingredient (4) to the granules, compress the mixture with a compression tablet machine to give a diameter of 7 mg containing 10 mg of ingredient (1) per tablet.
1000 mm tablets were produced.

Example 3 Production Method of Capsule of NPH4 Main Component Formulation (1) 5,6,7,8-Tetrahydroneopterin 10 g (2) Lactose 135 g (3) Cellulose Fine Powder 70 g (4) Magnesium Stearate 5 g 1000 Capsules 220g All ingredients are mixed and filled into 1000 gelatin capsules No. 3 (12th revised Japanese Pharmacopoeia), and each capsule has ingredient (1) 1
A capsule containing 0 mg was prepared.

Example 4 Effect of NPH4 in Sand Murine Cerebral Ischemia Model NPH4 was administered to a sand murine cerebral ischemia model, and changes in brain oxygen concentration during ischemia were expressed as changes in relative amount of oxygen-binding hemoglobin. It was observed by external spectroscopy (NIR). Furthermore, brain tissue sections were immunostained with an antibody against MAP2, which is a neuronal marker protein, and the degree of ischemic cell necrosis was evaluated to examine the brain protective effect of NPH4.

Bilateral carotid arteries of male sand rats weighing 60 to 80 g were ligated, and after 8 minutes of cerebral ischemia, reperfusion was performed. NPH4 was intraperitoneally administered at 3 mg / kg 10 minutes before the blood flow was blocked. The NIR was measured before the blood flow was blocked, and the measurement was recorded during the blocking for 8 minutes and for 10 minutes after the reperfusion. After completion of the ischemia experiment, the sand rat was awakened and then bred for 7 days. Under anesthesia, systemic perfusion was performed with a fixing reagent. After fixing the tissue, the brain was removed and immunostaining with an anti-MAP2 antibody was performed.

A typical example of the NIR measurement results is shown in FIG.
In both NPH4 administration group and non-administration group (n = 5), a decrease in oxygen-bound hemoglobin was observed immediately after the blood flow was blocked, and the blood flow returned to the normal value, but in the NPH4 non-administration group, after blood flow was resumed. A transient increase (rebound) of oxygen-bound hemoglobin was observed, suggesting a massive outbreak of active oxygen. This phenomenon persisted for over 6 minutes.
On the other hand, in the NPH4 administration group, such an excessive increase in brain oxygen concentration was not observed at all.

FIG. 2 shows the inhibitory effect of NPH4 on nerve cell death. One week after the ischemic treatment, immunostaining of the CA1 region of the hippocampus of the brain using MAP2 antibody was carried out for both groups.
In the H4 non-administration group, remarkable destruction of nerve cell architecture was observed. On the other hand, in the NPH4-administered group, almost no change was observed in the nerve cell construct image, and the normal state was maintained. Therefore, N
It was found that PH4 remarkably suppressed nerve cell death in cerebral ischemic injury.

From the above results, it has been clarified that NPH4 is a drug that remarkably reduces the extent of brain damage by eliminating a large amount of active oxygen generated in the cerebral ischemia model by its strong antioxidant action. became.

[0023]

INDUSTRIAL APPLICABILITY By the present invention, a cerebral circulatory disorder agent containing NPH4 as an active ingredient and having immediate effect could be provided.

[Brief description of drawings]

1 is a graph showing changes over time in the relative amount of oxygen-binding hemoglobin in the brain in each treatment group in the suppression of overproduction of oxygen-binding hemoglobin of NPH4 in sand rat cerebral ischemia-reperfusion injury in Example 4. Infrared spectrogram.

[Fig. 2] In Example 4, brain hippocampus CA1 showing the neuronal cell death inhibitory effect of NPH4 in the sand rat cerebral ischemia model.
Area neuron diagram.

Claims (1)

[Claims] 1. A general formula: A therapeutic agent for cerebral circulatory disorders comprising 5,6,7,8-tetrahydroneopterin represented by